This invention relates to the combination of muscarinic agonists with narcotic analgesics, non-steroidal anti-inflammatory drugs or other analgesic drugs and to their use as antinociception (pain relief) agents. In particular, the invention relates to a combination of a specific class of M4 selective muscarinic agonists with narcotic analgesics, non-steroidal anti-inflammatory drugs or other analgesic drugs.
Both narcotic analgesics (e.g. morphine) and non-steroidal anti-inflammatory drugs (NSAIDs) are well-known analgesics. Use of narcotic analgesics is limited by their ability to produce tolerance and addiction and their side effect profile. Side effects of narcotic analgesics include constipation, respiratory depression and nausea. NSAIDs are generally well tolerated but less efficacious analgesic agents.
Muscarinic agents have been shown to be effective analgesic agents in animal models with an efficacy similar to morphine but with much greater potency. The concept of using muscarinic agonists as potential analgesic agents for use in humans has been around for about five decades. Despite this there have been no muscarinic agonists approved for the treatment of pain. The primary reason for this has been their unacceptable side effect profile. A lack of understanding of the muscarinic receptor subtype mediating antinociception versus the side effects has further hampered work in this area. Recently however it has been shown that agonists which act selectively at the M4 receptor may provide good antinociception with an improved side effect profile (Ellis et al., The Journal of Pharmacology and Experimental Therapeutics, 288(3), 1999).
A class of M4 selective muscarinic agonists with reduced cholinergic side effects is described in WO 00/11001. These compounds are members of classes of azaadamantanes, azanoradamantanes and azahomoadamantanes.
Despite the work done in this field there remains a need for anti-nociceptive compositions having an improved analgesic profile without increasing side effects.
The present invention brings a solution in that it has now been found that a class of M4 selective muscarinic agonists when used in combination with additional analgesics enables an analgesic effect to be reached with concomitant reduction of undesirable side-effects compared to those side-effects experienced when either the M4 selective muscarinic agonists or the additional analgesics are administered alone in a concentration able of reaching the same analgesic effect. The additional analgesics may be narcotic analgesics, non-steroidal anti-inflammatory drugs (NSAID""s) or other analgesics. In particular embodiments, the class of M4 selective muscarinic agonists when used in combination with narcotic analgesics, non-steroidal anti-inflammatory drugs (NSAID""s) or other analgesics produces synergism or super-additivity in the analgesic profile without increasing side effect liabilities.
The present invention relates thus to a composition comprising at least one M4 selective muscarinic agonist selected from the azacyclic ring system having the formula I 
including geometrical isomers, enantiomers, diastereomers, racemates, acid addition salts, salts thereof with a pharmaceutically acceptable acid, and prodrugs thereof, wherein
Q is 
X is xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
V, W, Y and Z independently are CH or N;
n and m independently are 0, 1, 2, 3 or 4;
R1 and R2 are at any position on the azacyclic ring, including the point of attachment of the heterocycle Q, and independently are hydrogen, xe2x80x94OH, halogen, xe2x80x94NH2, carboxy, straight or branched C1-10-alkyl, C1-10-alkenyl, or C1-10-alkynyl, straight or branched C1-10-alkoxy, or straight or branched C1-10-alkyl substituted with xe2x80x94OH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR3R4, xe2x80x94NO2, xe2x80x94SOR3, xe2x80x94SO2R3, xe2x80x94COR3, xe2x80x94CO2R3, xe2x80x94CONH2, xe2x80x94CONHR3, xe2x80x94CONR3R4, or xe2x80x94CHxe2x95x90NOR3; or
R1 and R2 independently are phenyl, phenoxy, henzoyl, benzyl or benzyloxycarbonyl, each of which are unsubstituted or substituted with halogen, xe2x80x94CN, C1-10-alkyl, C1-10-alkoxy, or C1-10-alkylthio;
R is hydrogen, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94NH2, xe2x80x94NHR3, xe2x80x94NR3R4, xe2x80x94NO2, xe2x80x94SOR3, xe2x80x94SO2R3, xe2x80x94COR3, xe2x80x94CO2R3, xe2x80x94CONH2, xe2x80x94CONHR3, xe2x80x94CONR3R4, or xe2x80x94CNxe2x95x90NOR3; or
R is phenyl, phenoxy, benzoyl, benzyl or benzyloxycarbonyl, each of which are unsubstituted or substituted with halogen, xe2x80x94CN, C1-15-alkyl, C1-10-alkoxy, or C1-10-alkylthio; or
R is a 5 or 6 membered saturated, partly saturated or aromatic heterocyclic ring containing one to three heteroatoms; and
R3 and R4 independently are straight, branched, or cyclic C1-15-alkyl, C2-15-alkenyl, C2-15-alkynyl, or combinations thereof, or R3 and R4 independently are phenyl, phenoxy, benzoyl, benzyl or benzyloxycarbonyl groups, each of which are unsubstituted or substituted with H, halogen, xe2x80x94CN, C1-15-alkyl, C1-10-alkoxy, C1-10-alkylthio, or aryl; or
R3 and R4 independently are 5 or 6 membered saturated, partly saturated or aromatic heterocyclic rings containing one to three heteroatoms; and
further comprising one or more additional analgesics.
In preferred embodiments, the one or more additional analgesics produce a synergistic or super-additive effect (xe2x80x9csynergistic analgesics or super-additivexe2x80x9d).
In a preferred embodiment, the present invention relates to a composition as defined above wherein in formula I of the M4 selective muscarinic agonist n and m both are 1 and the azazyclic ring system has the structural formula: 
wherein
Q is: 
X is S,
Y and Z are N, and
R is OR3 or SR3.
In a more preferred embodiment, the present invention relates to a composition as defined above wherein R3 of the M4 selective muscarinic agonist is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3 or xe2x80x94CH2CH(CH3)2.
In a still more preferred embodiment, the invention relates to a composition comprising at least one M4 selective muscarinic agonist selected from the group consisting of, 3-(5-Aza-2-chlorotricyclo[3.3.1.1 less than 3,7 greater than ]dec-2-yl)-4-chloro-1,2,5-thiadiazole, 3-(5-Azatricyclo-[3.3.1.1 less than 3,7 greater than ]dec-2-yl)-4-chloro-1,2,5-thiadiazole, 3-(5-azatricyclo[3.3.1.1 less than 3,7 greater than ]dec-2-yl)-4-methoxy-1,2,5-thiadiazole, 3-(5-azatricyclo-[3.3.1.1 less than 3,7 greater than ]dec-2-yl)-4-ethoxy-1,2,5-thiadiazole, 3-(5-azatricyclo[3.3.1.1 less than 3,7 greater than ]dec-2-yl)-4-propoxy-1,2,5-thiadiazole, 3-(5-azatricyclo[3.3.1.1 less than 3,7 greater than ]dec-2-yl)-4-butoxy-1,2,5-thia-diazole, 3-(5-azatricyclo-[3.3.1.1 less than 3,7 greater than ]dec-2-yl)-4-(cyclopropylmethoxy)1,2,5-thiadiazole, 3-(5-azatricyclo-[3.3.1.1 less than 3,7 greater than ]dec-2-yl)-4-(2-methyl-propoxy)-1,2,5-thiadiazole, 4-[4-(propylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo[3.3.1.1 less than 3,7 greater than ]decane, 4-[4-(methylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo[3.3.1.1 less than 3,7 greater than ]decane, 4-[4-(ethylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo[3.3.1.1 less than 3,7 greater than ]decane, 4-[4-(butylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo-[3.3.1.1 less than 3,7 greater than ]decane, 4-[4-(2-methyl-propylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo-[3.3.1.1 less than 3,7 greater than ]decane, 4-[4-(cyclopropylmethylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo-[3.3.1.1 less than 3,7 greater than ]decane and
further comprising one or more additional analgesics.
In a most preferred embodiment, the invention relates to a composition comprising the M4 selective muscarinic agonist 4-s-[4-(propylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo[3.3.1.1 less than 3,7 greater than ]decane and further comprising one or more additional analgesics.
In a further preferred embodiment of the invention, the compositions further comprise a pharmaceutically acceptable carrier.
In another embodiment, the invention relates to a method of inducing analgesia, the method comprising co-administration of at least one M4 selective muscarinic agonist selected from the azacyclic ring system having the formula I 
including geometrical isomers, enantiomers, diastereomers, racemates, acid addition salts, salts thereof with a pharmaceutically acceptable acid, and prodrugs thereof, wherein
Q is 
X is xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
V, W, Y and Z independently are CH or N;
n and m independently are 0, 1, 2, 3 or 4;
R1 and R2 are at any position on the azacyclic ring, including the point of attachment of the heterocycle Q, and independently are hydrogen, xe2x80x94OH, halogen, xe2x80x94NH2, carboxy, straight or branched C1-10-alkyl, C1-10-alkenyl, or C1-10-alkynyl, straight or branched C1-10-alkoxy, or straight or branched C1-10-alkyl substituted with xe2x80x94OH, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94NH2, xe2x80x94NHR3, xe2x80x94NR3R4, xe2x80x94NO2, xe2x80x94SOR3, xe2x80x94SO2R3, xe2x80x94COR3, xe2x80x94CO2R3, xe2x80x94CONH2, xe2x80x94CONHR3, xe2x80x94CONR3R4, or xe2x80x94CNxe2x95x90NOR3; or
R1 and R2 independently are phenyl, phenoxy, benzoyl, benzyl or benzyloxycarbonyl, each of which are unsubstituted or substituted with halogen, xe2x80x94CN, C1-10-alkyl, C1-10-alkoxy, or C1-10-alkylthio;
R is hydrogen, halogen, xe2x80x94CN, xe2x80x94CHO, xe2x80x94OH, xe2x80x94OR3, xe2x80x94SR3, xe2x80x94NH2, xe2x80x94NHR3, xe2x80x94NR3R4, xe2x80x94NO2, xe2x80x94SOR3, xe2x80x94SO2R3, xe2x80x94COR3, xe2x80x94CO2R3, xe2x80x94CONH2, xe2x80x94CONHR3, xe2x80x94CONR3R4, or xe2x80x94CNxe2x95x90NOR3; or
R is phenyl, phenoxy, benzoyl, benzyl or benzyloxycarbonyl, each of which are unsubstituted or substituted with halogen, xe2x80x94CN, C1-15-alkyl, C1-10-alkoxy, or C1-10-alkylthio; or
R is a 5 or 6 membered saturated, partly saturated or aromatic heterocyclic ring containing one to three heteroatoms; and
R3 and R4 independently are straight, branched, or cyclic C1-15-alkyl, C2-15-alkenyl, C2-15-alkynyl, or combinations thereof, or R3 and R4 independently are phenyl, phenoxy, benzoyl, benzyl or benzyloxycarbonyl groups, each of which are unsubstituted or substituted with H, halogen, xe2x80x94CN, C1-15-alkyl, C1-10-alkoxy, C1-10-alkylthio, or aryl; or
R3 and R4 independently are 5 or 6 membered saturated, partly saturated or aromatic heterocyclic rings containing one to three heteroatoms; with
one or more additional analgesics.
The term xe2x80x9cco-administrationxe2x80x9d relates both to simultaneous administration and to immediate subsequent administration of at least one M4 selective muscarinic agonist and one or more additional analgesics. In the case of simultaneous administration, the at least one M4 selective muscarinic agonist and the one or more additional analgesics may be administered individually or in the form of a fixed combination, as described in the above sections.
Thus, in a particular embodiment, the invention relates to a method of inducing analgesia, the method comprising administering an analgesia-inducing amount of a composition as defined in the above sections to a mammal in need thereof.
The invention also relates to a composition as defined above for use as a medicament, preferably for use as an analgesic.
In a further embodiment the invention relates to the use of a composition as defined above for the manufacture of a medicament for the treatment of analgesia.
The term aryl as used herein refers to phenyl, substituted phenyl, or heteroaryl (as further defined below) wherein the substituent is halo, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, alkoxyalkyl, methylenedioxy, cyano, C(O)alkyl, carboxy, C(O)2alkyl, amide, amino, alkylamino and dialkylamino, and wherein the aryl group can have up to 3 substituents.
The term halo, as used herein, includes fluoro, chloro, bromo, and iodo.
The term heteroatom refers to N, S, or O.
The term heterocycle means a cycloalkyl moiety substituted in the ring by one or more heteroatoms.
The term heteroaryl and heteroaromatic, as used herein, refers to an aromatic moiety that includes at least one heteroatom in the aromatic ring.
The term M4 selective muscarinic agonists refers to agonists that have high affinity and agonist activity at the M4 receptor subtype but have low or very low agonist activity at the other muscarinic receptors subtypes M1, M2, M3 and M5. The M4 selective muscarinic agonists having the formula I according to the invention have a good therapeutic index, which is the ratio between desirable analgesic effects versus side effects.
The term synergistic or super-additive analgesic refers to any analgesics which in combination with the M4 selective muscarinic agonists having the formula I lead to potentiated pain relief without increasing side effect liabilities. The term is intended to include opioid analgesics, nonsteroidal anti-inflammatory agents (NSAIDs) and other analgesics.
The term opioid analgesic, as used herein, represents opioids and opioid antagonists. The term opioid represents natural or synthetic substances, that bind to opiate receptors and produce an agonist action.
The term opioid antagonist refers to opioid-like substances that bind to opiate receptors but produce little or no agonist activity. These substances are also effective pain relievers. The term opioid analgesic includes morphine, codeine, dihydrocodeine, meptazinol, dezocine, cyclazocine, tramadol, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, hydrocodone, oxymorphone, oxycodone, pentazocine, naloxone, nalorphine, naltrexone, butorphanol, nalbuphine and buprenorphine but is not limited thereto.
Preferred opioid analgesics are selected from morphine and codeine. The most preferred opioid analgesic is morphine.
The term nonsteroidal anti-inflammatory drugs (NSAIDs) refers to a heterogeneous group of drugs that are useful in the symptomatic treatment of inflammation and that have analgesic properties. It includes acetaminophen, the non-selective COX inhibitors such as aspirin, ibuprofen, indomethacin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ketoprofen, ketorolac, meclofenamic acid, mefenarnic acid, nabumetone, naproxen, oxaprozin, phenylbutazone piroxicam, sulindac, tolmetin, zomepirac and the selective COX-2 inhibitors such as NS-398, celecoxib and rofecoxib but is not limited thereto. Preferred nonsteroidal anti-inflammatory drugs are acetaminophen, ibuprofen, celoxicib and refoxicib.
The term other analgesics includes nicotinic agonists such as ABT-594, NMDA (N-methyl-D-aspartate) antagonists such as dextromethorphan, dextrorphan, amantadine, memantine, anti-epileptics such as gabapentin, levetiracetam, pregabalin and alpha adrenoceptor agonists such as clonidine but is not limited thereto.